Is COG7 p.Pro334Ser (c.1000C>T) pathogenic?

COG7 p.Pro334Ser (c.1000C>T) is classified Uncertain significance in COG7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-29). AlphaMissense: likely benign (0.0763); Very rare (popmax 0.00856%, nfe); Associated with COG7-related disorder.

What condition is associated with COG7 p.Pro334Ser (c.1000C>T)?

COG7 p.Pro334Ser (c.1000C>T) is associated with COG7-related disorder, COG7-congenital disorder of glycosylation (ClinVar).

How common is COG7 p.Pro334Ser (c.1000C>T) in the general population?

COG7 p.Pro334Ser (c.1000C>T) is very rare (popmax 0.00856%, nfe) (gnomAD).

What do computational predictors say about COG7 p.Pro334Ser (c.1000C>T)?

AlphaMissense predicts likely benign (score 0.0763) — an in-silico prediction, not a clinical call.

COG7 p.Pro334Ser

c.1000C>T · rs373631927 · VCV2067772

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0763 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00856%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

COG7-related disorder

Computational evidence

Protein change
AlphaMissense	0.0763	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	LLR -6.99	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.1	GERP -2.8, phastCons 0.49
Regional constraint	o/e 0.93	unconstrained · MANE · 64 kb · p 0.033 · regional, not allelic
Overall
CADD	11.33	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00856% European (non-Finnish) · 101/1,180,026 alleles

Filtering AF 0.00716% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00668%

Overall 0.00675% 109/1,614,094 alleles · very rare exomes 103/1,461,848 · genomes 6/152,246 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0112%	8,927
European (non-Finnish)grpmax	0.00856%	11,683
African / African-American	0.00133%	74,948

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: COG7
Protein: p.Pro334Ser
Coding: c.1000C>T
MANE Select: NM_153603
dbSNP: rs373631927
Type: single nucleotide variant
Location: chr16:23424758 (GRCh38)
Gene constraint: LOEUF 0.651 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.77

Full COG7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

COG7-related disorder

Also linked: COG7-congenital disorder of glycosylation

Similar variants

COG7 p.Pro334= Likely benign ★ same residue
COG7 c.318+1G>A Likely pathogenic ★★ same condition
COG7 p.Ala606Asp Pathogenic/Likely pathogenic ★★ ⚠ same condition
COG7 p.Arg444Ter Pathogenic/Likely pathogenic ★★ same condition
COG7 c.1475+4G>A Uncertain significance ★★ same condition
COG7 p.Ala194Val Uncertain significance ★★ ⚠ same condition
COG7 p.Ala222Thr Uncertain significance ★★ ⚠ same condition
COG7 p.Ala29Val Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cog7-p-pro334ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown